Novel inhibitors of eukaryotic elongation factor 2 kinase: in silico, synthesis and in vitro studies

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dc.authorscopusid55930443900
dc.authorscopusid22955598300
dc.authorscopusid56711736000
dc.authorscopusid57204631537
dc.authorscopusid55326408200
dc.authorscopusid8607330500
dc.authorscopusid6602877137
dc.contributor.authorÖnder, F.C.
dc.contributor.authorDurdağı, S.
dc.contributor.authorKahraman, N.
dc.contributor.authorUslu, T.N.
dc.contributor.authorKandemir, Hakan
dc.contributor.authorAtıcı, E.B.
dc.contributor.authorAy, M.
dc.date.accessioned2022-05-11T14:04:40Z
dc.date.available2022-05-11T14:04:40Z
dc.date.issued2021
dc.departmentFakülteler, Fen Edebiyat Fakültesi, Kimya Bölümü
dc.description.abstractEukaryotic elongation factor 2 kinase (eEF2K) is an unusual alpha kinase whose expression is highly upregulated in various cancers and contributes to tumor growth, metastasis, and progression. More importantly, eEF2K expression is associated with poor clinical outcome and shorter patient survival in breast, lung and ovarian cancers. Therefore, eEF2K is an emerging molecular target for development of novel targeted therapeutics and precision medicine in solid cancers. Currently, there are not any available potent and specific eEF2K inhibitors for clinical translation. In this study, we designed and synthesized a series of novel compounds with coumarin scaffold with various substitutions and investigated their effects in inhibiting eEF2K activity using in silico approaches and in vitro studies in breast cancer cells. We utilized an amide substitution at position 3 on the coumarin ring with their pharmacologically active groups containing pyrrolidine, piperidine, morpholine and piperazine groups with [sbnd](CH2)2[sbnd] bridged for aliphatic amides. Due to their ability to form covalent binding to the target enzyme, we also investigated the effects of boron containing groups on functionalized coumarin ring (3 compounds) and designed novel aliphatic and aromatic derivatives of coumarin scaffolds (10 compounds) and phenyl ring with boron groups (4 compounds). The Glide/SP module of the Maestro molecular modeling package was used to perform in silico analysis and molecular docking studies. According to our combined results, structure activity relationship (SAR) was performed in detail. Among the newly designed, synthesized, and tested compounds, our in vitro findings revealed that several compounds displayed a highly effective eEF2K inhibition at submicromolar concentrations in in vitro breast cancer cells. In conclusion, we identified novel compounds that can be used as eEF2K inhibitors and that they should be further evaluated by in vivo preclinical tumor models studies for antitumor efficacy and clinical translation. © 2021 Elsevier Inc.
dc.description.sponsorship215S008; Türkiye Bilimsel ve Teknolojik Araştirma Kurumu, TÜBITAK
dc.description.sponsorshipThis study was supported by The Scientific and Technological Research Council of Turkey (TUBITAK, Project No 215S008). FCO also thanks TUBITAK for scholarships (215S008 Project and BIDEB 2214A program). The authors thank to Çanakkale Onsekiz Mart University-COBILTUM Center Laboratory and Çankırı Karatekin University Research Center Laboratory and DEVA Holding A.Ş. for spectral analysis.
dc.description.sponsorshipThis study was supported by The Scientific and Technological Research Council of Turkey (TUBITAK, Project No 215S008). FCO also thanks TUBITAK for scholarships (215S008 Project and BIDEB 2214A program). The authors thank to ?anakkale Onsekiz Mart University-COBILTUM Center Laboratory and ?ank?r? Karatekin University Research Center Laboratory and DEVA Holding A.?. for spectral analysis. MA, BO and FCO designed and wrote the project. FCO and MA designed and synthesized compounds 2L-2Z and 3. SD performed in silico analysis. BO and NK performed western blot analysis. MA, HK and FCO designed compounds 4-6. The synthesis of 4-6 was performed by HK and TNU. Spectroscopic analysis for some compounds was performed by EBA. All authors wrote, read, reviewed and contributed to this article.
dc.identifier.doi10.1016/j.bioorg.2021.105296
dc.identifier.issn0045-2068
dc.identifier.pmid34488125
dc.identifier.scopus2-s2.0-85114181060
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://doi.org/10.1016/j.bioorg.2021.105296
dc.identifier.urihttps://hdl.handle.net/20.500.11776/4700
dc.identifier.volume116
dc.identifier.wosWOS:000701684500005
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorUslu, Tugce Nur
dc.institutionauthorKandemir, Hakan
dc.language.isoen
dc.publisherAcademic Press Inc.
dc.relation.ispartofBioorganic Chemistry
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.subject2H-chromene
dc.subjectBreast cancer
dc.subjectCoumarin carboxamide
dc.subjectCoumarin, benzopyran
dc.subjecteEF2K
dc.subjectEukaryotic elongation factor 2 kinase
dc.subjectMolecular modelling
dc.subjectEEF2K protein, human
dc.subjectelongation factor 2 kinase
dc.subjectprotein kinase inhibitor
dc.subjectchemical structure
dc.subjectchemistry
dc.subjectdose response
dc.subjectfemale
dc.subjecthuman
dc.subjectmetabolism
dc.subjectmolecular model
dc.subjectstructure activity relation
dc.subjectsynthesis
dc.subjecttumor cell line
dc.subjectCell Line, Tumor
dc.subjectDose-Response Relationship, Drug
dc.subjectElongation Factor 2 Kinase
dc.subjectFemale
dc.subjectHumans
dc.subjectModels, Molecular
dc.subjectMolecular Structure
dc.subjectProtein Kinase Inhibitors
dc.subjectStructure-Activity Relationship
dc.titleNovel inhibitors of eukaryotic elongation factor 2 kinase: in silico, synthesis and in vitro studies
dc.typeArticle

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